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An Xie, Michal Pawlowski, Feng Feng, Karol S. Bruzik, Haohua Qian, David R. Pepperberg; Enhancement Of GABA-elicited Responses Of Retinal Ganglion Cells by A Photo-isomerizable Compound. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1610.
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© ARVO (1962-2015); The Authors (2016-present)
Photo-regulation of postsynaptic receptors of inner retinal neurons may have potential as a vision restoration therapy in photoreceptor degenerative diseases, by enabling bypass of the deteriorated photoreceptors. GABAA receptors of retinal ganglion cells (RGCs) play a significant role in modulating the generation of RGC visual signals. GABA-elicited responses of RGCs are potentiated by propofol (2,6-diisopropylphenol),a known allosteric GABAA modulator (Ref. 1), and the activity of α1β2γ2 GABAA receptors expressed in Xenopus oocytes can be light-regulated by propofol derivatives that incorporate a photo-isomerizable azobenzene component (2,3). We have tested the action of one such compound, termed MPC088, on GABA responses of isolated RGCs. MPC088 consists of propofol joined at carbon 4 to a butyryl spacer that is amide-coupled to 4-(aminomethyl)-azobenzene-4'-(2-aminoethyl)carboxamide. As with unmodified azobenzene, UV light (wavelengths near 365 nm) drives trans MPC088 to the cis isomer, and visible (white) light drives cis to trans.
Isolated single RGCs were obtained from excised retinas of adult Sprague-Dawley rats and studied by whole-cell voltage-clamp recording.
RGC responses to a fixed concentration of GABA (3 µM) were increased by co-application of trans-dominant MPC088 (tMPC088). The extent of increase grew with tMPC088 concentration over the range of 1-10 µM. As normalized to the peak amplitude of the 3 µM GABA-alone response, that obtained with (3 µM GABA + 10 µM tMPC088) was 5.0 ± 2.2 (n=24). By comparison, co-application of 3 µM GABA and 10 µM propofol produced a normalized change of only 1.8 ± 0.5 (n=12). Supplementation with 100 µM bicuculline virtually eliminated the response to co-applied (3 µM GABA + 10 µM tMPC088); the average reduction was 98% (n=3). Pre-treatment of tMPC088 with UV light that reduced the abundance of trans isomer by ~50% or more significantly decreased the enhancement of the 3 µM GABA response from 5.7 ± 1.2 to 2.9 ± 1.0 (n=5) (p<0.001).
The data indicate that MPC088 enhances the GABA response of rat RGCs. This activity appears dependent on the relative level of the trans isomer and (from the bicuculline results) is mediated by GABAA receptors. The results encourage further study of the action of MPC088 on RGCs in vitro and in vivo. (1) Xie et al., 2010 ARVO. (2) Yue et al., 2010 ARVO. (3) Yue et al., 2010 Society for Neuroscience meeting.
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